Studies of two different agents show strong response, survival data

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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Two PD-L1 inhibitors, one approved and one investigational, demonstrated significant clinical activity in advanced urothelial cancers.

Both immunotherapeutic agents, atezolizumab and pembrolizumab, were reasonably well tolerated.

The data make a strong case for anti-PD 1 therapy in treating urothelial cancer according to expert opinion.

CHICAGO -- Two immunotherapeutic agents demonstrated activity in advanced urothelial cancer, extending the growing efficacy reach of the drugs to another cancer site, according to preliminary clinical trials.

More than a third of patients with advanced urothelial cancer responded to the investigational PD-L1 inhibitor atezolizumab (formerly MPDL3280A). The response rate increased to 50% in the subgroup of patients with the highest levels of PD-L1 expression, as reported here at the American Society of Clinical Oncology meeting.

"Atezolizumab has demonstrated promising clinical activity in a heavily pretreated metastatic urothelial bladder cancer cohort with encouraging survival and clinically meaningful response data," said Daniel Petrylak, MD, of Yale School of Medicine. "Atezolizumab was well tolerated with manageable side effects. There were no treatment-related deaths, and the grade 3/4 immune-mediated adverse event rate was 5%."

"The highly sensitive and specific SP142 immunohistochemistry assay measures PD-L1 expression on infiltrating cells, which may be a predictive biomarker for atezolizumab," he added.

Another study showed that two-thirds of patients had some degree of tumor shrinkage in response to treatment with pembrolizumab (Keytruda), an approved PD-1 inhibitor. More than a fourth of patients had objective responses, including three complete responses.

Petrylak reported findings from an ongoing phase Ia clinical trial involving patients with multiple types of advanced solid tumors, including almost 100 patients with advanced urothelial cancer. The trial is evaluating the safety and efficacy of atezolizumab by assay-confirmed PD-L1 expression and in unselected patients. The SP142 companion assay measures PD-L1 expression and quantifies expression into four categories (0-3). The assay detects PD-L1 expression in tumor cells and in tumor-infiltrating immune cells (IC), said Petrylak.

A majority of the patients with urothelial cancer had undergone cystectomy or nephroureterectomy. All but six patients had received platinum-based chemotherapy, and more than two-thirds had received two or more prior systemic therapies. More than 40% of the patients had no response or progressive disease within 3 months of their most recent systemic therapy.

Among 87 patients evaluable for response, tumors with all levels of PD-L1 expression responded to atezolizumab. Using IC to categorize PD-L1 expression level, investigators found that nine of 12 patients with IC3 expression had objective responses, as did 15 of 34 patients with IC2 expression. Of 26 patients whose tumors had IC2 expression, five (19%) responded to atezolizumab, and two of 15 patients with IC0 expression had objective responses. The IC2/3 subgroup had an overall response rate of 50%, including nine complete responses.

Median overall survival has yet to be reached but is currently estimated at 10 to 14 months for all patients (14 months in the IC2/3 subgroup).

In general, atezolizumab has been well tolerated. Treatment-emergent adverse events (all grades) occurring in at least 10% of patients include fatigue (16%), asthenia (13%), nausea (11%), decreased appetite (10%), and pruritus (10%). Grade 3/4 adverse events have occurred in seven patients, only elevated liver enzymes (AST) has occurred in as many as two patients.

The urothelial cancer patients treated with pembrolizumab were enrolled in an ongoing phase Ib trial that also includes patients with triple-negative breast cancer, head and neck cancer, and gastric cancer, said Elizabeth Plimack, MD, of Fox Chase Cancer Center in Philadelphia. Thus far, 33 patients with advanced urothelial cancer have been enrolled. All but eight of the urothelial cancer subgroup had received one or more prior systemic therapies.

Of 29 evaluable patients, eight (27.6%) achieved objective responses with pembrolizumab. An additional three patients had stable disease, resulting in a disease control rate of 37.9%.

In addition to the eight patients who met objective response criteria (≥30% tumor shrinkage), another 10 had lesser degrees of tumor regression.

The patients with urothelial cancer had a median progression-free survival and overall survival of 12.7 months.

Correlative studies showed that assessment of PD-L1 expression predicted likelihood of response to pembrolizumab. However, the study showed less than 100% concordance between tumor cell and associated inflammatory-cell expression.

Pembrolizumab was well tolerated in the cohort with urothelial cancer. The most common treatment-emergent adverse events were fatigue (18.2%) and peripheral edema (12.1%). Five patients had grade 3/4 adverse events, but no event occurred in more than one patient.

"In order to maximize detecting responders while minimizing the false-negative rate, scoring needs to take into account both PD-L1 positive tumor cells and PD-L1 positive tumor-associated inflammatory cells," said Plimack.

Taken together, the studies make a strong case for use of anti-PD 1 therapy in the treatment of urothelial cancer, said invited discussant Noah Hahn, MD, of Johns Hopkins.

"The overall response rates in these studies are quite impressive," said Hahn. "Both are more than double what we've seen from unselected previous trials. The overall survival stacks up quite well with historical data."

"I think we have expanded our therapeutic options for urothelial cancer patients," he added. "Clearly, we need to figure out the route to regulatory approval, but I think this is a new option that we have for these patients. Patient outcomes, I think, are improving, at least in our initial reports from two separate trials."

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